C O M M U N I C A T I O N S
Table 1. Products from the Proline-Catalyzed Mannich-Reaction
of Unmodified Ketones with N-PMP-Protected R-Imino Ethyl
Glyoxylate
environmentally friendly solvents under operationally simple reac-
tion conditions. In the laboratory, these reactions were readily
performed on a gram scale. Further studies addressing the scope
and applicability are currently under investigation and will be
disclosed in a full paper.
Acknowledgment. This study was supported in part by the NIH
(CA27489) and The Skaggs Institute for Chemical Biology.
Supporting Information Available: Complete analytical data for
all new compounds (PDF). This material is available free of charge
References
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(2) For recent reviews, see: (a) Cole, D. C. Tetrahedron 1994, 50, 9517. (b)
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EnantioselectiVe Synthesis of â-Amino Acids; Juaristi, E., Ed.; Wiley-
VCH: New York, 1997.
(3) Stoichiometric: (a) Enders, D.; Shilvock, J. P. Chem Soc. ReV. 2000, 29,
359. (b) Davis, F. A.; Kee, S.; Zhang, H.; Fanelli, D. L. J. Org. Chem.
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Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Houben-Weyl: New
York, 1995; E21b, p 1931. Catalytic: For an account comprising the
important work of Corey, Hoveyda, Jacobsen, Kobayashi, Lipton, and
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Nogami, H.; Kanai, M.; Shibasaki, M Tetrahedron Lett. 2001, 42, 279.
(4) (a) Seebach, D.; Hoffmann, M. Eur. J. Org. Chem. 1998, 1337. (b) Aoyagi,
Y.; Jain, R. P.; Williams, R. M. J. Am. Chem. Soc. 2001, 123, 3472 and
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K. V.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2992. (c)
Knudsen, K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.; Jørgensen,
K. A. J. Am. Chem. Soc. 2001, 123, 5843. (d) Hagiwara, E.; Fujii, A.;
Sodeoka, M. J. Am. Chem. Soc. 1998, 120, 2474. (e) Williams, R. M.;
Sinclair, P. J.; Zhai, D.; Chen, D. J. Am. Chem. Soc. 1988, 110, 1547. (f)
For the strategically similar nitro-Mannich reaction, see also: Yamada,
K.; Harwood, S. J.; Gro¨ger, H.; Shibasaki, M. Angew. Chem., Int. Ed.
Engl. 1999, 38, 3504.
(6) (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000,
122, 2395. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am.
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Lett. 2000, 41, 6951. (d) Betancort, J. M.; Sakthivel, K.; Thayumanavan,
R.; Barbas, C. F., III Tetrahedron Lett. 2001, 42, 4441. (e) Notz, W.;
Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F., III Tetrahedron Lett.
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(7) For addition reactions to imines, see: (a) Kobayashi, S.; Ishitani, H. Chem.
ReV. 1999, 99, 1069. (b) Hirabayashi, R.; Ogawa, C.; Sugiura, M.;
Kobayashi, S. J. Am. Chem. Soc. 2001, 123, 9493. (c) Ishitani, H.; Ueno,
M.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 8180 and references
therein. (d) List, B. J. Am. Chem. Soc. 2000, 122, 9336.
(8) The imine was preformed and isolated prior to the reaction. For its
preparation, see ref 5a. We have also investigated the one-pot three-
component Mannich reaction. In this case, however, the reaction does
not proceed to completeness and considerable amounts of the correspond-
ing aldol product are formed. PMP ) p-methoxyphenyl.
(9) This donor gave no products in related aldol reactions. See ref 6b.
(10) Hydroxyacetone also furnished excellent stereoselectivities in related aldol
reactions. See ref 6b and the following: Notz, W.; List, B. J. Am. Chem.
Soc. 2000, 122, 7386.
a PMP ) p-methoxyphenyl. b Isolated yields of pure product after column
chromatography. In a typical experiment, N-PMP-protected R-imino ethyl
glyoxylate (0.5 mmol) was dissolved in anhydrous DMSO (4 mL), the
corresponding ketone donor (1 mL) was added followed by L-proline (20
mol %), and the mixture was stirred for 2-24 h at room temperature.
Following aqueous workup with half-saturated ammonium chloride solution
and extraction with ethyl acetate, the organic layer was dried (MgSO4),
filtered, and concentrated and the residue purified by column chroma-
tography (silica, hexanes/ethyl acetate mixtures) to afford the corresponding
Mannich addition product. c dr ) syn/anti as determined by NMR. d The
ee values of products 1-7 were determined by chiral-phase HPLC analysis.
e Acetone was used as solvent.
Scheme 2. Further Modifications of Mannich Product ent-4a
(11) Acetone: 86% yield, 99% ee. CHCl3: 84%, 98% ee. EtOAc: 65%,
98% ee. Toluene: 81%, 83% ee. THF: 79%, 97% ee. 1,4-Dioxane: 81%,
98% ee.
(12) For this purpose, the following donors were studied: acetone, hydroxy-
acetone, cyclohexanone, and 2-butanone.
a Reagents and conditions: (a) PhI(OAc)2, MeOH, 0 °C, 30 min, 1 h;
1 N HCl, 0 °C, 30 min; (b) aqueous Na2CO3, Ac2O (64%), or Boc2O (68%).
(c) L-Selectride, THF, -78 °C, 89%.
(13) Only DMSO and CHCl3 provided satisfactory results in related aldol and
Mannich-type reactions. See refs 6b,e and 7d. In these cases, 20 mol %
catalyst and 20 vol % ketone donor were typically employed.
(14) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am.
Chem. Soc. 2001, 123, 10409-10410. The dr and ee were not affected
by this protocol. Removal of the keto group and ester cleavage of 9 pro-
vides access to (R)-cyclohexylglycine, which was recently posted on
yields with excellent regio-, diastereo-, and enantioselectivities. In
the case of 2-5 and 7, two adjacent stereogenic centers are created
simultaneously upon carbon-carbon bond-formation with complete
stereocontrol. Furthermore, the keto-functionality present in these
products offers a particularly attractive site for versatile modifica-
tions. Our methodology utilizes achiral, readily available, and rather
inexpensive starting materials, does not require any preactivation
of substrates or metal ion assistance, and can be carried out in
(15) See Supporting Information. Similar syn-selectivities in Mannich-type
reactions have been reported earlier. See refs 5a and 7b,d.
JA017270H
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